Reduced Steroid Synthesis in the Follicular Fluid of MTHFR 677TT Mutation Carriers: Effects of Increased Folic Acid Administration.

Objective To compare steroid profiles in the follicular fluid (FF) from women homozygous for the methylenetetrahydrofolate reductase (MTHFR) 677C>T mutation and wildtype controls and to correlate it with the folic acid administration scheme applied at the time of oocyte retrieval. Design Retrospective single center study. Subjects and Methods Infertile patients treated by using assisted reproductive techniques were genotyped routinely for the MTHFR 677C>T mutation. In 2006 they had received folic acid supplementation doses of 400 µg daily per os. This group was designated Group-400 (n = 10). From 2008 onwards, all of our infertility patients received a daily dose of 800 µg folic acid per os. Women from this group were designated Group-800 (n = 28). FF were collected and a panel of steroid hormones (estradiol, estrone, estriol, cortisol, progesterone, 17-OH progesterone, testosterone, androstenedione, aldosterone, DHEA, and DHEA-S) was measured by isotope dilution liquid chromatography-tandem mass spectrometry employing atmospheric pressure photo ionization (APPI). Results In Group-400, the FF hormone profile confirmed a significant reduction of estradiol in homozygous 677TT carriers (0.52 ± 0.08-fold, exact p = 0.032) and for the first time also revealed significantly reduced estriol concentrations in these individuals (0.54 ± 0.05-fold, p = 0.016), as compared to wildtype controls. In Group-800, no significant differences were found for concentrations of any of the steroid hormones between homozygous 677TT carriers and wildtype controls. Conclusions The current findings support and extend previous reports on reduced concentrations of specific steroid hormones in follicular fluids of homozygous MTHFR 677C>T mutation carriers. The restoration of the FF hormone profile by elevated-dose folic acid supplementation might impact performing ART in infertile women with the MTHFR 677TT-genotype. Further adequately powered studies are necessary to verify our finding and to demonstrate the clinical effect of enhanced folic supplementation on ovarian function.

Stable Isotope Pharmacokinetic Studies Provide Insight into Effects of Age, Sex, and Weight on Levothyroxine Metabolism.

BACKGROUND: This study sought to determine whether levothyroxine pharmacokinetics (PKs) are affected by age, weight, and sex. METHODS: A PK study was performed after administration of a tracer dose of carbon-13-labeled LT4 (13C-LT4). The study was conducted at an academic medical center. Adults of any age being treated with levothyroxine for hypothyroidism were enrolled in the study. A single dose of 13C-LT4 was administered. Eighteen serial plasma samples were collected. One sample was obtained before the 13C-LT4 dose, and the majority of the remaining samples were collected over the 120-hour period post dosing. 13C-LT4 concentration was quantified using liquid chromatography tandem mass spectrometry. PK analysis was conducted using a linear log trapezoidal non-compartmental analysis using Phoenix 6.4. RESULTS: Eight males and 33 females with a median age of 50 years (range 22-78 years) and median weight of 65.9 kg (range 50-150 kg) were enrolled in the study. The median 13C-LT4 dose administered was 100 µg (range 70-300 µg). The median oral clearance rate (CL/F), apparent volume of distribution (V/F), time to peak concentration (Tmax), and dose-normalized peak concentration (Cmax) of 13C-LT4 were estimated to be 0.712 L/h, 164.9 L, 4 h, and 7.5 ng/L/µg, respectively. The dose-normalized area under the concentration-time curve from time 0 to 120 hours and half-life of the terminal distribution phase were 0.931 ng.h/mL/µg and 172.2 h, respectively. There was no significant difference in any 13C-LT4 PK parameter between patients aged >60 years (n = 10) and patients aged ≤60 years (n = 31), nor was there a relationship between age as a continuous variable and 13C-LT4 PK parameters. Sex only affected CL/F, V/F, and dose-normalized Cmax in univariate analyses. However, after adjusting for weight, sex was no longer a significant covariate. Weight was a significant predictor for CL/F, V/F and dose-normalized Cmax of 13C-LT4 in multivariate analyses. CONCLUSION: Prior studies suggest that patient age affects levothyroxine dose requirement. This study did not identify an effect of age and suggests that age-related changes in levothyroxine pharmacokinetics may be mediated by age-related weight differences. Physicians should consider a patient's weight, rather than age, for estimating levothyroxine dosage requirement.

Phenols and parabens in relation to reproductive and thyroid hormones in pregnant women.

INTRODUCTION: Phenols and parabens are ubiquitous environmental contaminants. Evidence from animal studies and limited human data suggest they may be endocrine disruptors. In the current study, we examined associations of phenols and parabens with reproductive and thyroid hormones in 106 pregnant women recruited for the prospective cohort, "Puerto Rico Testsite for Exploring Contamination Threats (PROTECT)". METHODS: Urinary exposure biomarkers (bisphenol A, triclosan, benzophenone-3, 2,4-dichlorophenol, 2,5-dichlorophenol, butyl, methyl and propyl paraben) and serum hormone levels (estradiol, progesterone, sex hormone-binding globulin (SHBG), free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone) were measured at up to two time points during pregnancy (16-20 weeks and 24-28 weeks). We used linear mixed models to assess relationships between exposure biomarkers and hormone levels across pregnancy, controlling for urinary specific gravity, maternal age, BMI and education. In sensitivity analyses, we evaluated cross-sectional relationships between exposure and hormone levels stratified by study visit using linear regression. RESULTS: An IQR increase in methyl paraben was associated with a 7.70% increase (95% CI 1.50, 13.90) in SHBG. Furthermore, an IQR increase in butyl paraben as associated with an 8.46% decrease (95% CI 16.92, 0.00) in estradiol, as well as a 9.34% decrease (95% CI -18.31,-0.38) in estradiol/progesterone. Conversely, an IQR increase in butyl paraben was associated with a 5.64% increase (95% CI 1.26, 10.02) in FT4. Progesterone was consistently negatively associated with phenols, but none reached statistical significance. After stratification, methyl and propyl paraben were suggestively negatively associated with estradiol at the first time point (16-20 weeks), and suggestively positively associated with estradiol at the second time point (24-28 weeks). CONCLUSIONS: Within this ongoing birth cohort, certain phenols and parabens were associated with altered reproductive and thyroid hormone levels during pregnancy. These changes may contribute to adverse health effects in mothers or their offspring, but additional research is required.

Urinary phthalate metabolites in relation to maternal serum thyroid and sex hormone levels during pregnancy: a longitudinal analysis.

BACKGROUND: Increasing scientific evidence suggests that exposure to phthalates during pregnancy may be associated with an elevated risk of adverse reproductive outcomes such as preterm birth. Maternal endocrine disruption across pregnancy may be one pathway mediating some of these relationships. We investigated whether urinary phthalate metabolites were associated with maternal serum thyroid (free thyroxine [FT4], free triiodothyronine [FT3], and thyroid-stimulating hormone [TSH]), and sex (estradiol, progesterone, and sex hormone-binding globulin [SHBG]) hormone levels at multiple time points during pregnancy. METHODS: Preliminary data (n = 106) were obtained from an ongoing prospective birth cohort in Northern Puerto Rico. We collected urine and serum sample at the first and third study visits that occurred at 18 +/- 2 and 26 +/- 2 weeks of gestation, respectively. To explore the longitudinal relationships between urinary phthalate metabolites and serum thyroid and sex hormone concentrations, we used linear mixed models (LMMs) adjusted for prepregnancy body mass index (BMI) and maternal age. An interaction term was added to each LMM to test whether the effect of urinary phthalate metabolites on serum thyroid and sex hormone levels varied by study visit. In cross-sectional analyses, we stratified BMI- and age-adjusted linear regression models by study visit. RESULTS: In adjusted LMMs, we observed significant inverse associations between mono-3-carboxypropyl phthalate (MCPP) and FT3 and between mono-ethyl phthalate (MEP) and progesterone. In cross-sectional analyses by study visit, we detected stronger and statistically significant inverse associations at the third study visit between FT3 and MCPP as well as mono-carboxyisooctyl phthalate (MCOP); also at the third study visit, significant inverse associations were observed between FT4 and metabolites of di-(2-ethylhexyl) phthalate (DEHP). The inverse association between MEP and progesterone was consistent across study visits. CONCLUSIONS: In this group of pregnant women, urinary phthalate metabolites may be associated with altered maternal serum thyroid and sex hormone levels, and the magnitude of these effects may depend on the timing of exposure during gestation.

Thyroid functional disease: an under-recognized cardiovascular risk factor in kidney disease patients.

Thyroid functional disease, and in particular hypothyroidism, is highly prevalent among chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients. In the general population, hypothyroidism is associated with impaired cardiac contractility, endothelial dysfunction, atherosclerosis and possibly higher cardiovascular mortality. It has been hypothesized that hypothyroidism is an under-recognized, modifiable risk factor for the enormous burden of cardiovascular disease and death in CKD and ESRD, but this has been difficult to test due to the challenge of accurate thyroid functional assessment in uremia. Low thyroid hormone levels (i.e. triiodothyronine) have been associated with adverse cardiovascular sequelae in CKD and ESRD patients, but these metrics are confounded by malnutrition, inflammation and comorbid states, and hence may signify nonthyroidal illness (i.e. thyroid functional test derangements associated with underlying ill health in the absence of thyroid pathology). Thyrotropin is considered a sensitive and specific thyroid function measure that may more accurately classify hypothyroidism, but few studies have examined the clinical significance of thyrotropin-defined hypothyroidism in CKD and ESRD. Of even greater uncertainty are the risks and benefits of thyroid hormone replacement, which bear a narrow therapeutic-to-toxic window and are frequently prescribed to CKD and ESRD patients. In this review, we discuss mechanisms by which hypothyroidism adversely affects cardiovascular health; examine the prognostic implications of hypothyroidism, thyroid hormone alterations and exogenous thyroid hormone replacement in CKD and ESRD; and identify areas of uncertainty related to the interplay between hypothyroidism, cardiovascular disease and kidney disease requiring further investigation.

3,3'-Diiodothyronine concentrations in hospitalized or thyroidectomized patients: results from a pilot study.

OBJECTIVE: To determine if various medical conditions affect the serum concentrations of 3,3'-diiodothyronine (3,3'-T2). METHODS: A total of 100 patients who were recruited from a group of inpatients and outpatients with a diverse range of medical conditions, donated a single blood sample that was assayed for thyroid hormone derivatives using liquid-chromatography tandem mass spectrometry (LC-MS/MS). The associations between 3,3'-T2 concentrations and physiologic data and medical conditions were assessed. RESULTS: Higher quartiles of 3,3'-T2 concentrations (quartile 1: 2.01-7.48, quartile 2: 7.74-12.4, quartile 3: 12.5-17, quartile 4: 17.9-45.8 pg/mL) were associated with decreasing occurrence of critical illness (58%, 11%, 0%, 8%), stroke (29%, 7.7%, 4%, 0%), critical care unit hospitalization (75%, 39%, 8.3 %, 12%), and inpatient status (83%, 42%, 8%, 12%) (all P<.001). The same quartiles were associated with increasing frequency of thyroidectomy (4%, 12%, 17%, 60%). In multivariate analyses, after adjustment for age and sex, inpatient status was associated with decreasing concentrations of 3,3'-T2 (46% decrease for inpatients with 95% confidence interval [CI] 32-57%, P<.0001). Thyroidectomy was associated with increasing concentrations of 3,3'-T2 (29% increase (CI 0.5-66%, P = .049). CONCLUSION: We observed associations between inpatient status and reduced 3,3'-T2 concentrations. This appears to be a global change associated with illness, rather than an association with specific medical conditions. We also observed higher 3,3'-T2 concentrations in athyreotic outpatients receiving thyroid-stimulating hormone (TSH) suppression therapy. This demonstrates that there is production of 3,3'-T2 from levothyroxine (LT4) in extrathyroidal tissues. Conversion of thyroxine (T4) to 3,3'-T2 via both triiodothyronine (T3) and reverse triiodothyronine (rT3) pathways may prevent excessive T3 concentrations in such patients.

P450 oxidoreductase *28 (POR*28) and tacrolimus disposition in pediatric kidney transplant recipients--a pilot study.

BACKGROUND: Both age and CYP3A5 genotype are important determinants of tacrolimus disposition in pediatric kidney transplant recipients. In a recent study in adults, POR*28 was associated with increased dosing requirements early after transplant of CYP3A5-expressing kidney transplant recipients. The authors aimed to evaluate the additional contribution of POR*28 to early tacrolimus disposition in pediatric kidney transplant recipients. METHODS: Retrospective data of 43 pediatric kidney transplant recipients up to 14 days posttransplant were evaluated on tacrolimus dose and tacrolimus predose blood concentrations. Recipient POR*28 and CYP3A5 genotype were determined. RESULTS: CYP3A5 expressers carrying at least 1 POR*28 allele had on average 18.3% lower tacrolimus predose concentrations and 20.2% lower concentration/dose ratios compared with CYP3A5 expressers with POR*1/*1 genotype (P = 0.002 and P = 0.001, respectively). In CYP3A5 nonexpressers, tacrolimus disposition did not significantly differ between POR genotypes. CONCLUSIONS: In this small cohort of pediatric kidney transplant recipients, POR*28 genotype seems to explain part of the variability found in tacrolimus disposition, in addition to age and CYP3A5 genotype. This finding should be validated in a larger population, and it would be worthwhile to evaluate the clinical impact of this genotype.

Thyrotropin isoforms: implications for thyrotropin analysis and clinical practice.

Serum thyrotropin (TSH) is considered the single most sensitive and specific measure of thyroid function in the general population owing to its negative logarithmic association with free triiodothyronine and free thyroxine concentrations. It is therefore often the test of choice for screening, diagnosis, and monitoring of primary hypothyroidism. Serum TSH concentrations can be analyzed quantitatively using third-generation immunoassays, whereas its bioactivity can be measured by TSH activity assays in cell culture. Theoretically, if serum TSH concentrations are directly related to TSH activity, the two tests should yield comparable results. However, on occasion, the results are discordant, with serum concentrations being higher than TSH biological activity. This review focuses on the dissociation between the clinical state and serum TSH concentrations and addresses clinically important aspects of TSH analysis.

Violence against women and gastroschisis: a case-control study.

BACKGROUND: Gastroschisis, a birth defect characterized by herniated fetal abdominal wall, occurs more commonly in infants born to teenage and young mothers. Ischemia of the vascular vitelline vessels is the likely mechanism of pathogenesis. Given that chronic stress and violence against women are risk factors for cardiovascular disease we explored whether these may represent risk factors for gastroschisis, when they occur during pregnancy. A case-control study was conducted, with 15 incident cases of children born with gastroschisis in the Region of Murcia, Spain, from December 2007 to June 2013. Forty concurrent controls were recruited at gestation weeks 20-24 or post-partum. All mothers of cases and controls completed a comprehensive, in-person, 'green sheet' questionnaire on environmental exposures. RESULTS: Mothers of children with gastroschisis were younger, smoked more cigarettes per week relative to controls, were exposed to higher amounts of illegal drugs, and suffered from domestic violence more frequently than the controls. Multivariable logistic regression analysis highlights periconceptional 'gender-related violence' (OR: 16.6, 95% CI 2.7 to 101.7) and younger maternal age (OR 1.1, 95% CI 1.0-1.3). CONCLUSIONS: Violence against pregnant women is associated with birth defects, and should be studied in more depth as a cause-effect teratogenic. Psychosocial risk factors, including gender-based violence, are important for insuring the health and safety of the pregnant mother and the fetus.

CYP3A4*22 and CYP3A combined genotypes both correlate with tacrolimus disposition in pediatric heart transplant recipients.

BACKGROUND: Tacrolimus metabolism depends on CYP3A4 and CYP3A5. We aimed to determine the relationship between the CYP3A4*22 polymorphism and combined CYP3A genotypes with tacrolimus disposition in pediatric heart transplant recipients. METHODS: Sixty pediatric heart transplant recipients were included. Tacrolimus doses and trough concentrations were collected in the first 14 days post-transplantation. CYP3A phenotypes were defined as extensive (CYP3A5*1 + CYP3A4*1/*1 carriers), intermediate (CYP3A5*3/*3 + CYP3A4*1/*1 carriers) or poor (CYP3A5*3/*3 + CYP3A4*22 carriers) metabolizers. RESULTS: CYP3A4*22 carriers needed 30% less tacrolimus (p = 0.016) to reach similar target concentrations compared with CYP3A4*1/*1 (n = 56) carriers. Poor CYP3A metabolizers required 17% (p = 0.023) less tacrolimus than intermediate and 48% less (p < 0.0001) than extensive metabolizers. Poor metabolizers showed 18% higher dose-adjusted concentrations than intermediate (p = 0.35) and 193% higher than extensive metabolizers (p < 0.0001). CONCLUSION: Analysis of CYP3A4*22, either alone or in combination with CYP3A5*3, may help towards individualization of tacrolimus therapy in pediatric heart transplant patients.

The Use of TSH in Determining Thyroid Disease: How Does It Impact the Practice of Medicine in Pregnancy?

During the last four decades, there have been considerable advances in the efficacy and precision of serum thyroid function testing. The development of the third generation assays for the measurement of serum thyroid stimulating hormone (TSH, thyrotropin) and the log-linear relationship with free thyroxine (T4) established TSH as the hallmark of thyroid function testing. While it is widely accepted that TSH outside of the normal range is consistent with thyroid dysfunction, a vast multitude of additional factors must be considered before an accurate clinical diagnosis can be made. This is especially important during pregnancy, when the thyroid is under considerable additional pregnancy-related demands requiring significant maternal physiological changes. This paper examines serum TSH measurement in pregnancy and some associated potential confounding factors.

Congenital fibrosarcoma and history of prenatal exposure to petroleum derivatives.

Congenital fibrosarcoma (CFS) is a rare fibrous tissue malignancy that usually presents in the first few years of life. It is unique among human sarcomas in that it has an excellent prognosis. We describe a temporal clustering of a number of cases of CFS and investigate the possible associated prenatal risk factors. The Pediatric Environmental History, a questionnaire developed in our clinic that is instrumental in determining environmental risk factors for tumor-related disease, was essential in documenting the presence or absence of risk factors considered as human carcinogens. We found a history of exposure to petroleum products in four cases of CFS that occurred at a greater than expected rate in a short time frame-an apparent cancer cluster. We call attention to the possibility that exposure to petroleum products raises the risk of developing CFS. While future studies should focus on systematic investigation of CFS and its underlying mechanisms, this report suggests the need for proactive measures to avoid exposure to solvents and petroleum products during pregnancy.

Teratology public affairs committee position paper: iodine deficiency in pregnancy.

Iodine deficiency is an important nutritional deficiency, with more than 2 billion people worldwide estimated to be at risk. The developing fetus and young children are particularly at risk. During pregnancy and lactation, iodine requirements increase, whether in iodine-poor or iodine-sufficient countries, making the mother and the developing fetus vulnerable. The American Thyroid Association (ATA) recommends 250 micrograms per day of iodine intake for pregnant and lactating women. The thyroid gland is able to adapt to the changes associated with pregnancy as long as sufficient iodine is present. Dietary intake is the sole source of iodine, which is essential to the synthesis of thyroid hormones. Iodine is found in multiple dietary sources including iodized salt, dairy products, seaweed, and fish. Prenatal vitamins containing iodine are a good source of iodine, but iodine content in multivitamin supplements is highly variable. Congenital hypothyroidism is associated with cretinism. Clinical hypothyroidism has been associated with increased risk of poor perinatal outcome including prematurity, low birth weight, miscarriage, preeclampsia, fetal death, and impaired fetal neurocognitive development. Subclinical hypothyroidism is also associated with poor pregnancy outcomes and potential fetal neurocognitive deficits, but the data are more variable than those for clinical hypothyroidism. We concur with the ATA recommendation that all pregnant and lactating women should ingest (through diet and supplements) 250 micrograms of iodine daily. To achieve this goal, we recommend that all pregnant and lactating women take daily iodine supplementation of 150 micrograms.

TSH - Clinical Aspects of its Use in Determining Thyroid Disease in the Elderly. How Does it Impact the Practice of Medicine in Aging?

The last four decades have seen enormous growth in the efficacy of serum thyroid stimulating hormone (thyrotropin, TSH) assay methodology, establishing TSH as the hallmark of thyroid testing. At the center of the considerations is the strong inverse correlation between serum thyrotropin and free thyroxine concentrations. While it is widely accepted that elevated serum TSH concentrations are consistent with thyroid dysfunction, a vast multitude of additional factors must be considered before an accurate clinical diagnosis can be made followed by an appropriate treatment. Epidemiological studies have demonstrated slightly elevated serum TSH concentrations among the elderly population. There is, however, a debate whether these elevated TSH levels reflect an increased prevalence of hypothyroidism among the elderly or a normal aspect of healthy aging. A comprehensive analysis of the many variables associated with this debate and TSH measurement as a diagnostic tool in aging should provide insight into the clinical efforts to diagnose and treat thyroid disease, particularly in the elderly population.

Innovative studies in women by use of stabilized isotopes in pregnancy.

Pharmacokinetic studies are conducted in order to determine drug absorption, distribution, metabolism and excretion. This knowledge serves to help determine the appropriate and timely use of medications and is also an important step in providing individualized therapeutics according to patient characteristics, such as disease state and genotypes of drug metabolizing enzymes. An innovative way of conducting pharmacokinetic research in pregnancy is presented, with the drug levothyroxine (LT4). The stable, non-radioactive Carbon-13 isotope was used to prepare a derivative of LT4, which was then used to determine the pharmacokinetics of the drug in 9 pregnant women serving as their own controls. Of 9 study subjects, 6 returned to participate in the post partum (non-pregnant) portion of the study. The median time to peak blood level was determined to be at 8 hours post dose. The AUC(0-∞) results were significantly higher during pregnancy than in the same woman approximately 6 months post partum. The increase in LT4 AUC during pregnancy could be attributed to a decrease in LT4 clearance. Additionally, a large variability in the pharmacokinetics of LT4 was found in pregnant women, and a relatively narrower range of variability in non-pregnant women. In order to solidify these findings, a larger group of patients is required. In addition, the mechanisms responsible for the gestational differences in pharmacokinetics need to be investigated.

Age and CYP3A5 genotype affect tacrolimus dosing requirements after transplant in pediatric heart recipients.

BACKGROUND: Tacrolimus is one of the commonly used immunosuppressive drugs for pediatric heart transplants. Large variation exists in pharmacokinetics during the direct post-transplant period, resulting in an increased risk of adverse events. Limited data are available on the interaction of age, CYP3A5 and ABCB1 genotype, and disease severity on the variation in disposition and outcome in pediatric heart transplant recipients. METHOD: We studied the relationship between age and CYP3A5 and ABCB1 genotype and the Pediatric Risk of Mortality (PRISM) score on tacrolimus dose (mg/kg), steady-state trough concentrations, and concentration/dose ratio, as well as rejection and renal function for 14 days after heart transplant in children. RESULTS: Tacrolimus was administered to 39 children (median age, 6.0 years) after transplant. A correlation was found between the age at the time of transplant and the tacrolimus dosing requirements (r(s) = -0.447, p = 0.004) and the concentration/dose ratio (r(s) = 0.351, p = 0.029). CYP3A5 expressors required median (interquartile range) higher doses of tacrolimus (0.14 [0.09] vs 0.06 [0.04] mg/kg/12 hours, p = 0.001), and had lower concentration/dose ratios (45.34 [44.54] vs 177.78 [145.38] ng/ml per mg/kg/12 hours, p < 0.0001). This relationship was not seen with the ABCB1 genotype. Age and CYP3A5 genotype predicted the tacrolimus dosing requirements as well as the concentration/dose ratio (R(2) = 0.351, p = 0.001 and R(2) = 0.521, p < 0.001). No relationship was found between any of the CYP3A5 or ABCB1 genotypes and the estimated glomerular filtration rate. CONCLUSION: Younger age and CYP3A5 expressor genotype were independently associated with higher dosing requirements and lower tacrolimus concentration/dose ratios.

The interactions of age, genetics, and disease severity on tacrolimus dosing requirements after pediatric kidney and liver transplantation.

PURPOSE: In children, data on the combined impact of age, genotype, and disease severity on tacrolimus (TAC) disposition are scarce. The aim of this study was to evaluate the effect of these covariates on tacrolimus dose requirements in the immediate post-transplant period in pediatric kidney and liver recipients. METHODS: Data were retrospectively collected describing tacrolimus disposition, age, CYP3A5 and ABCB1 genotype, and pediatric risk of mortality (PRISM) scores for up to 14 days post-transplant in children receiving liver and renal transplants. Initial TAC dosing was equal in all patients and adjusted using therapeutic drug monitoring. We determined the relationship between covariates and tacrolimus disposition. RESULTS: Forty-eight kidney and 42 liver transplant recipients (median ages 11.5 and 1.5 years, ranges 1.5-17.7 and 0.05-14.8 years, respectively) received TAC post-transplant. In both transplant groups, younger children (<5 years) needed higher TAC doses than older children [kidney: 0.15 (0.07-0.35) vs. 0.09 (0.02-0.20) mg/kg/12h, p = 0.046, liver: 0.12 (0.04-0.32) vs. 0.09 (0.01-0.18) mg/kg/12h, p = 0.038]. In kidney but not liver transplants, CYP3A5 expressors needed significantly higher TAC doses than nonexpressors [0.15 (0.07-0.20) vs. 0.09 (0.02-0.35) mg/kg/12h, P = 0.001]. In these patients, age and CYP3A5 genotype were independently associated with TAC dosing requirement. In liver, but not kidney transplant patients, homozygous ABCB1 T-T-T haplotype carriers needed higher TAC doses than noncarriers [0.26 (0.15-0.32) vs. 0.11 (0.01-0.25) mg/kg/12h, p = 0.013]. CONCLUSION: CYP3A5 genotype may explain variation in tacrolimus disposition early after transplant in pediatric kidney recipients, independent of age-related variation. In contrast, in pediatric liver recipients, variation in tacrolimus disposition appears related to age and ABCB1 genotype. These findings illustrate the importance of the interplay among age, genotype, and transplant organ on tacrolimus disposition.